Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation

The Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine

The impact of promoting revised UK low-risk drinking guidelines on alcohol consumption: interrupted time series analysis

Background: The UK’s Chief Medical Officers revised the UK alcohol drinking guidelines in 2016 to ≤ 14 units per week (1 unit = 10 ml/8 g ethanol) for men and women. Previously, the guideline stated that men should not regularly consume more than 3–4 units per day and women should not regularly consume more than 2–3 units per day. Objective: To evaluate the impact of promoting revised UK drinking guidelines on alcohol consumption. Design: Interrupted time series analysis of observational data. Setting: England, March 2014 to October 2017. Participants: A total of 74,388 adults aged ≥ 16 years living in private households in England. Interventions: Promotion of revised UK low-risk drinking guidelines. Main outcome measures: Primary outcome – alcohol consumption measured by the Alcohol Use Disorders Identification Test – Consumption score. Secondary outcomes – average weekly consumption measured using graduated frequency, monthly alcohol consumption per capita adult (aged ≥ 16 years) derived from taxation data, monthly number of hospitalisations for alcohol poisoning (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision: T51.0, T51.1 and T51.9) and assault (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision: X85–Y09), and further measures of influences on behaviour change. Data sources: The Alcohol Toolkit Study, a monthly cross-sectional survey and NHS Digital’s Hospital Episode Statistics. Results: The revised drinking guidelines were not subject to large-scale promotion after the initial January 2016 announcement. An analysis of news reports found that mentions of the guidelines were mostly factual, and spiked during January 2016. In December 2015, the modelled average Alcohol Use Disorders Identification Test – Consumption score was 2.719 out of 12.000 and was decreasing by 0.003 each month. After the January 2016 announcement, Alcohol Use Disorders Identification Test – Consumption scores did not decrease significantly (β = 0.001, 95% confidence interval –0.079 to 0.099). However, the trend did change significantly such that scores subsequently increased by 0.005 each month (β = 0.008, 95% confidence interval 0.001 to 0.015). This change is equivalent to 0.5% of the population moving each month from drinking two or three times per week to drinking four or more times per week. Secondary analyses indicated that the change in trend began 6 months before the guideline announcement. The secondary outcome measures showed conflicting results, with no significant changes in consumption measures and no substantial changes in influences on behaviour change, but immediate reductions in hospitalisations of 7.3% for assaults and 15.4% for alcohol poisonings. Limitations: The pre-intervention data collection period was only 2 months for influences on behaviour change and the graduated frequency measure. Our conclusions may be generalisable only to scenarios in which guidelines are announced but not promoted. Conclusions: The announcement of revised UK low-risk drinking guidelines was not associated with clearly detectable changes in drinking behaviour. Observed reductions in alcohol-related hospitalisations are unlikely to be attributable to the revised guidelines. Promotion of the guidelines may have been prevented by opposition to the revised guidelines from the government's alcohol industry partners or because reduction in alcohol consumption was not a government priority or because practical obstacles prevented independent public health organisations from promoting the guidelines. Additional barriers to the effectiveness of guidelines may include low public understanding and a need for guidelines to engage more with how drinkers respond to and use them in practice. Trial registration: Current Controlled Trials ISRCTN15189062. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 8, No. 14. See the NIHR Journals Library website for further project information

Effects on alcohol consumption of announcing and implementing revised UK low-risk drinking guidelines: findings from an interrupted time series analysis

Background: In January 2016, the UK announced and began implementing revised guidelines for low-risk drinking of 14 units (112 g) per week for men and women. This was a reduction from the previous guidelines for men of 3–4 units (24–32 g) per day. There was no large-scale promotion of the revised guidelines beyond the initial media announcement. This paper evaluates the effect of announcing the revised guidelines on alcohol consumption among adults in England. / Methods: Data come from a monthly repeat cross-sectional survey of approximately 1700 adults living in private households in England collected between March 2014 and October 2017. The primary outcomes are change in level and time trend of participants’ Alcohol Use Disorders Identification Test—Consumption (AUDIT-C) scores. / Results: In December 2015, the modelled average AUDIT-C score was 2.719 out of 12 and was decreasing by 0.003 each month. After January 2016, AUDIT-C scores increased immediately but non-significantly to 2.720 (β=0.001, CI −0.079 to 0.099) and the trend changed significantly such that scores subsequently increased by 0.005 each month (β=0.008, CI 0.001 to 0.015), equivalent to 0.5% of the population increasing their AUDIT-C score by 1 point each month. Secondary analyses indicated the change in trend began 7 months before the guideline announcement and that AUDIT-C scores reduced significantly but temporarily for 4 months after the announcement (β=−0.087, CI −0.167 to 0.007). / Conclusions: Announcing new UK drinking guidelines did not lead to a substantial or sustained reduction in drinking or a downturn in the long-term trend in alcohol consumption, but there was evidence of a temporary reduction in consumption

Neuromuscular Blockade with Rocuronium Bromide Increases the Tolerance of Acute Normovolemic Anemia in Anesthetized Pigs

Background: The patient's individual anemia tolerance is pivotal when blood transfusions become necessary, but are not feasible for some reason. To date, the effects of neuromuscular blockade (NMB) on anemia tolerance have not been investigated. Methods: 14 anesthetized and mechanically ventilated pigs were randomly assigned to the Roc group (3.78 mg/kg rocuronium bromide followed by continuous infusion of 1 mg/kg/min, n = 7) or to the Sal group (administration of the corresponding volume of normal saline, n = 7). Subsequently, acute normovolemic anemia was induced by simultaneous exchange of whole blood for a 6% hydroxyethyl starch solution (130/0.4) until a sudden decrease of total body O-2 consumption (VO2) indicated a critical limitation of O-2 transport capacity. The Hb concentration quantified at this time point (Hb(crit)) was the primary end-point of the protocol. Secondary endpoints were parameters of hemodynamics, O-2 transport and tissue oxygenation. Results: Hb(crit) was significantly lower in the Roc group (2.4 +/- 0.5 vs. 3.2 +/- 0.7 g/dl) reflecting increased anemia tolerance. NMB with rocuronium bromide reduced skeletal muscular VO2 and total body O-2 extraction rate. As the cardiac index increased simultaneously, total body VO2 only decreased marginally in the Roc group (change of VO2 relative to baseline -1.7 +/- 0.8 vs. 3.2 +/- 1.9% in the Sal group, p < 0.05). Conclusion: Deep NMB with rocuronium bromide increases the tolerance of acute normovolemic anemia. The underlying mechanism most likely involves a reduction of skeletal muscular VO2. During acellular treatment of an acute blood loss, NMB might play an adjuvant role in situations where profound stages of normovolemic anemia have to be tolerated (e.g. bridging an unexpected blood loss until blood products become available for transfusion). Copyright (C) 2011 S. Karger AG, Base

Correlates of substance abuse treatment completion among disadvantaged communities in Cape Town, South Africa

BACKGROUND: Completion of substance abuse treatment is a proximal indicator of positive treatment outcomes. To design interventions to improve outcomes, it is therefore important to unpack the factors contributing to treatment completion. To date, substance abuse research has not examined the factors associated with treatment completion among poor, disadvantaged communities in developing countries. This study aimed to address this gap by exploring client-level factors associated with treatment completion among poor communities in South Africa. METHODS: Secondary data analysis was conducted on cross-sectional survey data collected from 434 persons residing in poor communities in Cape Town, South Africa who had accessed substance abuse treatment in 2006. RESULTS: Multiple regression analyses revealed that therapeutic alliance, treatment perceptions, abstinence-specific social support, and depression were significant partial predictors of treatment completion. CONCLUSIONS: Findings suggest that treatment completion rates of individuals from poor South African communities can be enhanced by i) improving perceptions of substance abuse treatment through introducing quality improvement initiatives into substance abuse services, ii) strengthening clients' abstinence-oriented social networks and, iii) strengthening the counselor-client therapeutic alliance

DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells.

In addition to their well-known function in apoptosis, caspases are also important in several nonapoptotic processes. How caspase activity is restrained and shut down under such nonapoptotic conditions remains unknown. Here, we show that Drosophila melanogaster inhibitor of apoptosis protein 2 (DIAP2) controls the level of caspase activity in living cells. Animals that lack DIAP2 have higher levels of drICE activity. Although diap2-deficient cells remain viable, they are sensitized to apoptosis following treatment with sublethal doses of x-ray irradiation. We find that DIAP2 regulates the effector caspase drICE through a mechanism that resembles the one of the caspase inhibitor p35. As for p35, cleavage of DIAP2 is required for caspase inhibition. Our data suggest that DIAP2 forms a covalent adduct with the catalytic machinery of drICE. In addition, DIAP2 also requires a functional RING finger domain to block cell death and target drICE for ubiquitylation. Because DIAP2 efficiently interacts with drICE, our data suggest that DIAP2 controls drICE in its apoptotic and nonapoptotic roles.P.S. Ribeiro is supported by a PhD fellowship (SFRH/BD/15219/2004) from the Fundação para a Ciência e Tecnologia and F. Leulier is supported by a Human Frontier Science Program fellowship (LT-0177/2004). E. Kuranaga and M. Miura are supported in part by grants from the Japanese Ministry of Education, Science, Sports, Culture and Technology (19109003, 17025010, 19040006, 19041026, and 19044013) and the Takeda Science Foundation

Unravelling the alcohol harm paradox: a population-based study of social gradients across very heavy drinking thresholds

Background: There is consistent evidence that individuals in higher socioeconomic status groups are more likely to report exceeding recommended drinking limits, but those in lower socioeconomic status groups experience more alcohol-related harm. This has been called the ‘alcohol harm paradox’. Such studies typically use standard cut-offs to define heavy drinking, which are exceeded by a large proportion of adults. Our study pools data from six years (2008–2013) of the population-based Health Survey for England to test whether the socioeconomic distribution of more extreme levels of drinking could help explain the paradox. Methods: The study included 51,498 adults from a representative sample of the adult population of England for a cross-sectional analysis of associations between socioeconomic status and self-reported drinking. Heavy weekly drinking was measured at four thresholds, ranging from 112 g+/168 g + (alcohol for women/men, or 14/21 UK standard units) to 680 g+/880 g + (or 85/110 UK standard units) per week. Heavy episodic drinking was also measured at four thresholds, from 48 g+/64 g + (or 6/8 UK standard units) to 192 g+/256 g + (or 24/32 UK standard units) in one day. Socioeconomic status indicators were equivalised household income, education, occupation and neighbourhood deprivation. Results: Lower socioeconomic status was associated with lower likelihoods of exceeding recommended limits for weekly and episodic drinking, and higher likelihoods of exceeding more extreme thresholds. For example, participants in routine or manual occupations had 0.65 (95 % CI 0.57–0.74) times the odds of exceeding the recommended weekly limit compared to those in ‘higher managerial’ occupations, and 2.15 (95 % CI 1.06–4.36) times the odds of exceeding the highest threshold. Similarly, participants in the lowest income quintile had 0.60 (95 % CI 0.52–0.69) times the odds of exceeding the recommended weekly limit when compared to the highest quintile, and 2.30 (95 % CI 1.28–4.13) times the odds of exceeding the highest threshold. Conclusions: Low socioeconomic status groups are more likely to drink at extreme levels, which may partially explain the alcohol harm paradox. Policies that address alcohol-related health inequalities need to consider extreme drinking levels in some sub-groups that may be associated with multiple markers of deprivation. This will require a more disaggregated understanding of drinking practice

The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles

Caspases provide vital links in non-apoptotic regulatory networks controlling inflammation, compensatory proliferation, morphology and cell migration. How caspases are activated under non-apoptotic conditions and process a selective set of substrates without killing the cell remain enigmatic. Here we find that the Drosophila unconventional myosin CRINKLED (CK) selectively interacts with the initiator caspase DRONC and regulates some of its non-apoptotic functions. Loss of CK in the arista, border cells or proneural clusters of the wing imaginal discs affects DRONC-dependent patterning. Our data indicate that CK acts as substrate adaptor, recruiting SHAGGY46/GSK3-β to DRONC, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity. Similarly, the mammalian CK counterpart, MYO7A, binds to and impinges on CASPASE-8, revealing a new regulatory axis affecting receptor interacting protein kinase-1 (RIPK1)>CASPASE-8 signalling. Together, our results expose a conserved role for unconventional myosins in transducing caspase-dependent regulation of kinases, allowing them to take part in specific signalling events

How managers can build trust in strategic alliances: a meta-analysis on the central trust-building mechanisms

Trust is an important driver of superior alliance performance. Alliance managers are influential in this regard because trust requires active involvement, commitment and the dedicated support of the key actors involved in the strategic alliance. Despite the importance of trust for explaining alliance performance, little effort has been made to systematically investigate the mechanisms that managers can use to purposefully create trust in strategic alliances. We use Parkhe’s (1998b) theoretical framework to derive nine hypotheses that distinguish between process-based, characteristic-based and institutional-based trust-building mechanisms. Our meta-analysis of 64 empirical studies shows that trust is strongly related to alliance performance. Process-based mechanisms are more important for building trust than characteristic- and institutional-based mechanisms. The effects of prior ties and asset specificity are not as strong as expected and the impact of safeguards on trust is not well understood. Overall, theoretical trust research has outpaced empirical research by far and promising opportunities for future empirical research exist

Effect of simvastatin on bone markers in osteopenic women: a placebo-controlled, dose-ranging trial [ISRCTN85429598]

BACKGROUND: Hydroxymethylglutaryl coenzyme A reductase inhibitors increase new bone formation in vitro and in rodents. Results of epidemiologic analyses evaluating the association between use of these cholesterol-lowering drugs, bone mineral density and fracture have been mixed. METHODS: Women (n = 24) with osteopenia, assessed by broad band ultrasound attenuation, were randomized to simvastatin 20 mg, 40 mg or identical-appearing placebo for 12 weeks. Fasting lipid profiles and biochemical markers of bone formation (bone-specific alkaline phosphatase) and resorption (N-telopeptides and C-terminal propeptide of type 1 collagen) were measured at baseline, 6 and 12 weeks. RESULTS: Plasma low density lipoprotein-cholesterol concentration fell 7%, 39% (p < 0.01 vs baseline) and 47% (p < 0.01 vs baseline) after 12 weeks of treatment with placebo, simvastatin 20 mg and 40 mg, respectively. At baseline, bone marker concentrations were similar in the three treatment groups. At 6 and 12 weeks, bone marker concentrations were not different from baseline, and no significant differences in bone marker concentrations were observed between treatment groups at either 6 or 12 weeks. CONCLUSION: Among osteopenic women, treatment with simvastatin for 12 weeks did not affect markers of bone formation or resorption